In the United States, fetal alcohol syndrome (FAS) affects 12,000 babies each year and the rate of frequent drinking during pregnancy has increased four-fold between 1991 and 1995 (MMWR 46:346-50 (1997)). Maternal alcohol consumption is the most commonly identifiable non-genetic cause of mental retardation. In addition, consuming over 3 drinks per week in the first trimester has been shown to double the risk of miscarriage (Windham et al., Epidemiology, 8:509-14 (1997)). An increase in free radical formation has been implicated in the pathogenesis of alcohol-induced central nervous system dysfunction in FAS. Ethanol treatment in cell culture depresses cell viability and generates reactive oxygen intermediates including superoxide, hydrogen peroxide and hydroxyl anions (Guerri et al., Free Radicals in Diagnostic Medicine, Plenum Press, New York, 291-305 (1994)). Acute alcohol exposure has been shown to increase superoxide generation and decrease extraperoxisomal catalase activity, decreasing Cu, Zn-superoxide dismutase activity (Nordmann et al., Free Radical Biology and Medicine 12:219-40 (1992)).
The most devastating effects of alcohol exposure occur during organogenesis and development of the nervous system (Armant et al., Sem. Perinatol., 20:127-39 (1996)), during the time when vasoactive intestinal peptide (VIP) has been shown to regulate mouse embryonic growth (Gressens et al., Nature, 362:155-8 (1993)). There are known interactions between alcohol and VIP, a neuropeptide that is a regulator of early postimplantation mouse embryonic growth (Gressens et al., J. Clin. Invest. 94:2020-2027 (1994)). In pregnant mice, both alcohol and VIP antagonist treatment may result in some of the features of FAS, including fetal growth restriction and microcephaly. Interactions between alcohol and VIP include a decrease in VIP mRNA in the suprachiasmatic nucleus with alcohol exposure (Maderia et al., J. Neurosci., 17:1302-19 (1997)), and a decrease in VIP binding in rat enterocytes after chronic alcohol consumption (Jimenez et al., Gen. Pharmac., 23:607-11 (1992)). Ethanol has also been shown to result in cell death in the neuroepithelium (Gressens et al., Alc. & Alc., 27:219-26 (1992)), which is a prominent site of VIP binding (Hill et al., J. Comp. Neurol., 342:186-205 (1994)).
For individuals who were exposed to alcohol in utero, they may suffer from various mental and physical defects associated with fetal alcohol syndrome. For example, they may suffer from growth retardations; physical, mental, and behavioral abnormalities; central nervous system impairment, including developmental delay, small head size, and speech or language delay; and facial abnormalities.
In view of its severe and lifelong impact on the fetus, fetal alcohol syndrome is a major public concern. Although educating the public, in particular pregnant women, regarding consumption of alcohol and its effect on the fetus and refraining from drinking during pregnancy are the obvious, sensible approach to resolving this problem, this approach alone has not been effective as illustrated by the alarming statistics set forth above. Another method which can be used in conjunction with educating the public is approaching this problem clinically, i.e., intervening against alcohol induced damage by treating pregnant women with prophylactic compounds. Therefore, there is a need to identify and isolate compounds which can reduce fetal alcohol syndrome. The identification and isolation of new compounds would allow aid in the reduction and prevention of fetal alcohol syndrome and other related medical conditions.